DESCRIPTION (Taken from the Investigator's Abstract) Environmental factors are thought to play a role in development of neurodegenerative diseases such as Parkinson's Disease (PD), although the mechanisms remain unknown. The environmental contribution is likely a complex one involving multiple factors. Also, the responses to environmental stressors are likely not to be uniform across the population, but to reflect interactions with genetic factors that exacerbate effects in subsets of the population. Inhaled manganese (Mn) can enter the central nervous system (CNS) directly via the olfactory epithelium and distribute through the CNS. Mn and other metals produce PD-like symptoms in occupational exposures, and individuals with family histories of PD can be more susceptible (iron). Mn and iron (Fe) utilize the same transporter, and therefore may interact, although whether synergistically or competitively remains in questions. Because not all animals show uptake across the olfactory epithelium, this model system could provide insight to factors controlling sensitivity within the population. An interdisciplinary team will study uptake, distribution and clearance of inhaled Mn, its relationship to distribution of constitutive metals in the CNS, and to the development of neurodegeneration within dopaminergic systems involved in PD. Experimental manipulations will assess factors potentially altering epithelial permeability by inducing inflammation in the olfactory epithelium. As well, Mn/Fe interactions will be examined using Fe dietary supplements to produce Fe overload. The role of defects in clearance of damaged intracellular proteins will be studied using a mouse transgenic model that is ubiquitin dominant-negative. Markers of neurotoxicity will include neurodegenration; density, intensity and numbers of dopaminergic cell bodies and terminals; apoptosis; oxidative status of nigral neurons; and neuroinflammation in olfactory and dopaminergic systems in the brain and olfactory epithelium. The results of these studies viewed from the multiple perspectives of team members should clarify factors controlling CNS entry of inhaled toxicants, potential interactions of environmental exposures in potentially sensitive subsets of individuals; and the relationship to neurodegeneration. Ultimately, such approaches should help to identify markers of sensitive sub-populations or periods of sensitivity to inhaled neurotoxicants.